Effect of Human Recombinant Alkaline Phosphatase on 7-Day Creatinine Clearance in Patients With Sepsis-Associated Acute Kidney Injury

Abstract

IMPORTANCE Sepsis-associated acute kidney injury (AKI) adversely affects long-term kidney outcomes and survival. Administration of the detoxifying enzyme alkaline phosphatase may improve kidney function and survival. OBJECTIVE To determine the optimal therapeutic dose, effect on kidney function, and adverse effects of a human recombinant alkaline phosphatase in patients who are critically ill with sepsis-associated AKI. DESIGN, SETTING, AND PARTICIPANTS The STOP-AKI trial was an international (53 recruiting sites), randomized, double-blind, placebo-controlled, dose-finding, adaptive phase 2a/2b study in 301 adult patients admitted to the intensive care unit with a diagnosis of sepsis and AKI. Patients were enrolled between December 2014 and May 2017, and follow-up was conducted for 90 days. The final date of follow-up was August 14, 2017. INTERVENTIONS In the intention-to-treat analysis, in part 1 of the trial, patients were randomized to receive recombinant alkaline phosphatase in a dosage of 0.4 mg/kg (n = 31), 0.8 mg/kg (n = 32), or 1.6 mg/kg (n = 29) or placebo (n = 30), once daily for 3 days, to establish the optimal dose. The optimal dose was identified as 1.6 mg/kg based on modeling approaches and adverse events. In part 2, 1.6 mg/kg (n = 82) was compared with placebo (n = 86). MAIN OUTCOMES AND MEASURES The primary end point was the time-corrected area under the curve of the endogenous creatinine clearance for days 1 through 7, divided by 7 to provide a mean daily creatinine clearance (AUC 1-7 ECC). Incidence of fatal and nonfatal (serious) adverse events ([S]AEs) was also determined. RESULTS Overall, 301 patients were enrolled (men, 70.7%; median age, 67 years [interquartile range {IQR}, 59-73]). From day 1 to day 7, median ECC increased from 26.0 mL/min (IQR, 8.8 to 59.5) to 65.4 mL/min (IQR, 26.7 to 115.4) in the recombinant alkaline phosphatase 1.6-mg/kg group vs from 35.9 mL/min (IQR, 12.2 to 82.9) to 61.9 mL/min (IQR, 22.7 to 115.2) in the placebo group (absolute difference, 9.5 mL/min [95% CI, −23.9 to 25.5]; P = .47). Fatal adverse events occurred in 26.3% of patients in the 0.4-mg/kg recombinant alkaline phosphatase group; 17.1% in the 0.8-mg/kg group, 17.4% in the 1.6-mg/kg group, and 29.5% in the placebo group. Rates of nonfatal SAEs were 21.0% for the 0.4-mg/kg recombinant alkaline phosphatase group, 14.3% for the 0.8-mg/kg group, 25.7% for the 1.6-mg/kg group, and 20.5% for the placebo group. CONCLUSIONS AND RELEVANCE Among patients who were critically ill with sepsis-associated acute kidney injury, human recombinant alkaline phosphatase compared with placebo did not significantly improve short-term kidney function. Further research is necessary to assess other clinical outcomes.

Sepsis associated acute kidney injury

“…Although the study did not show a decrease in the primary endpoint of time corrected AUC of creatinine clearance for days 1 to 7, it did show decreased mortality in patients receiving alkaline phosphatase. More stage 3 AKI occurred in patients receiving alkaline phosphatase (11/111; 9.9%) than in those receiving placebo (5/116; 4.3%) 161. However, given the decreased 28 day mortality (17.4% in patients receiving 1.6 mg/kg compared with 29.5% of those in the placebo group), some possibility exists that although it is not a treatment for SA-AKI, recombinant alkaline phosphatase may play a role in the treatment of sepsis itself.…”

“…Alkaline phosphatase has been thought to be effective through the direct dephosphorylation of endotoxin leading to attenuated inflammation and organ dysfunction and improved survival rates. A recent international, randomized, double blind, placebo controlled, dose finding adaptive phase IIa/IIb study included 301 adults with SA-AKI 161. In the dose finding portion of the trial, 120 patients were randomized to receive recombinant alkaline phosphatase in a dose of 0.4, 0.8, or 1.6 mg/kg of the drug or placebo, with 1.6 mg/kg being determined to be the optimal dose.…”

Effects of intestinal alkaline phosphatase on intestinal barrier function in a cecal ligation and puncture (CLP)‐induced mouse model for sepsis

“…In the first two trials, treatment with IAP improved renal parameters, and decreased serum CRP and interleukin (IL)‐6 levels, but had no effect on mortality. In a more recent large multicenter trial, the improvement of short‐term kidney function could not be confirmed …”

“…In humans, the effect of IAP on acute kidney injury during sepsis has been investigated in three phase II clinical trials . In the first two trials, treatment with IAP improved renal parameters, and decreased serum CRP and interleukin (IL)‐6 levels, but had no effect on mortality.…”

“…17,20,[26][27][28][29][30][31][32] In humans, the effect of IAP on acute kidney injury during sepsis has been investigated in three phase II clinical trials. [33][34][35] In the first two trials, treatment with IAP improved renal parameters, and decreased serum CRP and interleukin (IL)-6 levels, but had no effect on mortality. In a more recent large multicenter trial, the improvement of short-term kidney function could not be confirmed.…”